WO2000029448A2 - Proteines humaines a domaines hydrophobes et adn codant pour ces proteines - Google Patents

Proteines humaines a domaines hydrophobes et adn codant pour ces proteines Download PDF

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Publication number
WO2000029448A2
WO2000029448A2 PCT/JP1999/006412 JP9906412W WO0029448A2 WO 2000029448 A2 WO2000029448 A2 WO 2000029448A2 JP 9906412 W JP9906412 W JP 9906412W WO 0029448 A2 WO0029448 A2 WO 0029448A2
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protein
present
amino acid
sequences
proteins
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PCT/JP1999/006412
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WO2000029448A3 (fr
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Seishi Kato
Tomoko Kimura
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Sagami Chemical Research Center
Protegene Inc.
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Priority claimed from JP32625598A external-priority patent/JP2007222001A/ja
Application filed by Sagami Chemical Research Center, Protegene Inc. filed Critical Sagami Chemical Research Center
Priority to AU11819/00A priority Critical patent/AU1181900A/en
Priority to EP99972227A priority patent/EP1161536A1/fr
Publication of WO2000029448A2 publication Critical patent/WO2000029448A2/fr
Publication of WO2000029448A3 publication Critical patent/WO2000029448A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants

Definitions

  • the present invention relates to human proteins having hydrophobic domains, DNAs encoding these proteins, and expression vectors for these DNAs as well as eukaryotic cells expressing these DNAs.
  • the proteins of the present invention can be employed as pharmaceuticals or as antigens for preparing antibodies against these proteins.
  • the human cDNAs of the present invention can be utilized as probes for genetic diagnosis and gene sources for gene therapy.
  • the cDNAs can be utilized as gene sources for large-scale production of the proteins encoded by these cDNAs.
  • Cells into which these genes are introduced to express secretory proteins or membrane proteins in large quantity can be utilized for detection of the corresponding receptors or ligands, screening of novel small molecule pharmaceuticals and the like.
  • membrane proteins play important roles, as signal receptors, ion channels, transporters and the like in the material transport and the signal transduction through the cell membrane.
  • Examples thereof include receptors for various cytokines, ion channels for the sodium ion, the potassium ion, the chloride ion and the like, transporters for saccharides and amino acids and the like.
  • the genes for many of them have already been cloned. It has been clarified that abnormalities of these membrane proteins are involved in a number of previously cryptogenic diseases. Therefore, discovery of a new membrane protein is expected to lead to elucidation of the causes of many diseases, so that isolation of new genes encoding the membrane proteins has been desired.
  • a general method is the so-called expression cloning method, in which a cDNA library is introduced into eukaryotic cells to express cDNAs, and the cells secreting, or expressing on the surface of membrane, the protein having the activity of interest are then screened.
  • a cDNA library is introduced into eukaryotic cells to express cDNAs, and the cells secreting, or expressing on the surface of membrane, the protein having the activity of interest are then screened.
  • genes for proteins with known functions can be cloned by using this method.
  • a secretory protein or a membrane protein possesses at least one hydrophobic domain within the protein. After synthesis in the ribosome, such domain works as a secretory signal or remains in the phospholipid membrane to be entrapped in the membrane. Accordingly, if the existence of a highly hydrophobic domain is observed in the amino acid sequence of a protein encoded by a cDNA when the whole base sequence of the full-length cDNA is determined, it is considered that the cDNA encodes a secretory protein or a membrane protein.
  • the main object of the present invention is to provide novel human proteins having hydrophobic domains, DNAs encoding these proteins, and expression vectors for these DNAs as well as transformed eukaryotic cells that are capable of expressing these DNAs.
  • Fig. 1 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP02539.
  • Fig. 2 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP02770.
  • Fig. 3 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP02869.
  • Fig. 4 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP02956.
  • Fig. 5 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP02962.
  • Fig. 6 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP03014.
  • Fig. 7 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP10608.
  • Fig. 8 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP10609.
  • Fig. 9 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP10611.
  • Fig. 10 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP10617.
  • Fig. 11 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP02837.
  • Fig. 12 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP02991.
  • Fig. 13 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP03063.
  • Fig. 14 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP03091.
  • Fig. 15 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP03092.
  • Fig. 16 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP03116.
  • Fig. 17 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP10618.
  • Fig. 18 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP10619.
  • Fig. 19 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP10622.
  • Fig. 20 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP10625.
  • Fig. 21 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP02883.
  • Fig. 22 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP03140.
  • Fig. 23 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP10628.
  • Fig. 24 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP10629.
  • Fig. 25 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP10635.
  • Fig. 26 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP10636.
  • Fig. 27 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP10640.
  • Fig. 28 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP10644.
  • Fig. 29 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP10656.
  • Fig. 30 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP10672.
  • Fig. 31 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP03194.
  • Fig. 32 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP03219.
  • Fig. 33 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP03236.
  • Fig. 34 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP03237.
  • Fig. 35 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP03267.
  • Fig. 36 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP03270.
  • Fig. 37 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP03298.
  • Fig. 38 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP10631.
  • Fig. 39 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP10658.
  • Fig. 40 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP10663.
  • Fig. 41 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP03165.
  • Fig. 42 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP03266.
  • Fig. 43 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP03287.
  • Fig. 44 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP10665.
  • Fig. 45 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP10669.
  • Fig. 46 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP10670.
  • Fig. 47 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP10671.
  • Fig. 48 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP10673.
  • Fig. 49 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP10675.
  • Fig. 50 illustrates the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP10683.
  • the present invention provides a human protein having hydrophobic domain(s), namely a protein comprising any one of an amino acid sequence selected from the group consisting of SEQ ID NOS: 1 to 10, 31 to 40, 61 to 70, 91 to 100, and 121 to 130.
  • the present invention provides a DNA encoding the above-mentioned protein, exemplified by a cDNA comprising any one of a base sequence selected from the group consisting of SEQ ID NOS: 11 to 30, 41 to 60, 71 to 90, 101 to 120 and 131 to 150 as well as an expression vector that is capable of expressing such DNA by in vitro translation or in eukaryotic cells and a transformed eukaryotic cell that is capable of expressing such DNA and of producing the above-mentioned protein.
  • a cDNA comprising any one of a base sequence selected from the group consisting of SEQ ID NOS: 11 to 30, 41 to 60, 71 to 90, 101 to 120 and 131 to 150 as well as an expression vector that is capable of expressing such DNA by in vitro translation or in eukaryotic cells and a transformed eukaryotic cell that is capable of expressing such DNA and of producing the above-mentioned protein.
  • the proteins of the present invention can be obtained, for example, by a method for isolating proteins from human organs, cell lines or the like, a method for preparing peptides by the chemical synthesis based on the amino acid sequence of the present invention, or a method for producing proteins by the recombinant DNA technology using the DNAs encoding the hydrophobic domains of the present invention.
  • the method for producing proteins by the recombinant DNA technology is preferably employed.
  • the proteins can be expressed in vitro by preparing an RNA by in vitro transcription from a vector having the cDNA of the present invention, and then carrying out in vitro translation using this RNA as a template.
  • introduction of the translated region into a suitable expression vector by the method known in the art may lead to expression of a large amount of the encoded protein in prokaryotic cells such as Escherichla coli, Bacillus subtilis, etc., and eukaryotic cells such as yeasts, insect cells, mammalian cells, etc.
  • prokaryotic cells such as Escherichla coli, Bacillus subtilis, etc.
  • eukaryotic cells such as yeasts, insect cells, mammalian cells, etc.
  • the protein of the present invention can be produced in vitro by introducing the translated region of this cDNA into a vector having an RNA polymerase promoter, and then adding the vector to an in vitro translation system such as a rabbit reticulocyte lysate or a wheat germ extract, which contains an RNA polymerase corresponding to the promoter.
  • an in vitro translation system such as a rabbit reticulocyte lysate or a wheat germ extract, which contains an RNA polymerase corresponding to the promoter.
  • the RNA polymerase promoters are exemplified by T7, T3, SP6 and the like.
  • the vectors containing these RNA polymerase promoters are exemplified by pKAl, pCDM8, pT3/T7 18, pT7/3 19, pBluescript II and the like.
  • the protein of the present invention can be expressed in the secreted form or the form incorporated in the microsome membrane when a canine pancreas microsome or the like is added to the reaction system.
  • the protein of the present invention is produced by expressing the DNA in a microorganism such as Escherichia coli etc .
  • a recombinant expression vector in which the translated region of the cDNA of the present invention is introduced into an expression vector having an origin which is capable of replicating in the microorganism, a promoter, a ribosome-binding site, a cDNA-cloning site, a terminator and the like is constructed.
  • the resulting transformant is grown, whereby the protein encoded by the cDNA can be produced in large quantity in the microorganism.
  • a protein fragment containing any translated region can be obtained by adding an initiation codon and a termination codon in front of and behind the selected translated region to express the protein.
  • the protein can be expressed as a fusion protein with another protein. Only the portion of the protein encoded by the cDNA can be obtained by cleaving this fusion protein with a suitable protease.
  • the expression vectors for Escherichia coli are exemplified by the pUC series, pBluescript II, the pET expression system, the pGEX expression system and the like.
  • the protein of the present invention is produced by expressing the DNA in eukaryotic cells
  • the protein of the present invention can be produced as a secretory protein, or as a membrane protein on the cell- membrane surface, by introducing the translated region of the cDNA into an expression vector for eukaryotic cells that has a promoter, a splicing region, a poly(A) addition site and the like, and then introducing the vector into the eukaryotic cells.
  • the expression vectors are exemplified by pKAl, pED6dpc2, pCDM8, pSVK3, pMSG, pSVL, pBK-CMV, pBK-RSV, EBV vectors, pRS, pYES2 and the like.
  • eukaryotic cells to be used in general include mammalian cultured cells such as monkey kidney COS7 cells, Chinese hamster ovary CHO cells and the like, budding yeasts, fission yeasts, silkworm cells, Xenopus oocytes and the like. Any eukaryotic cells may be used as long as they are capable of expressing the proteins of the present invention.
  • the expression vector can be introduced into the eukaryotic cells by using a method known in the art such as the electroporation method, the calcium phosphate method, the liposome method, the DEAE- dextran method and the like.
  • the protein of interest can be isolated from the culture and purified by a combination of separation procedures known in the art.
  • separation procedures include treatment with a denaturing agent such as urea or a detergent, sonication, enzymatic digestion, salting-out or solvent precipitation, dialysis, centrifugation, ultrafiltration, gel filtration, SDS-PAGE, isoelectric focusing, ion-exchange chromatography, hydrophobic chromatography, affinity chromatography, reverse phase chromatography and the like.
  • the proteins of the present invention also include peptide fragments (of 5 amino acid residues or more) containing any partial amino acid sequences in the amino acid sequences represented by SEQ ID NOS: 1 to 10, 31 to 40, 61 to 70, 91 to 100, and 121 to 130. These peptide fragments can be utilized as antigens for preparation of antibodies.
  • proteins of the present invention those having the signal sequences are secreted in the form of mature proteins after the signal sequences are removed. Therefore, these mature proteins shall come within the scope of the protein of the present invention.
  • the N-terminal amino acid sequences of the mature proteins can be easily determined by using the method for the determination of cleavage site of a signal sequence [JP 8-187100 A].
  • membrane proteins undergo the processing on the cell surface to be converted to the secreted forms.
  • proteins or peptides in the secreted forms shall also come within the scope of the protein of the present invention.
  • sugar chain-binding sites are present in the amino acid sequences of the proteins
  • expression of the proteins in appropriate eukaryotic cells affords the proteins to which sugar chains are attached. Accordingly, such proteins or peptides to which sugar chains are attached shall also come within the scope of the protein of the present invention.
  • the DNAs of the present invention include all the DNAs encoding the above-mentioned proteins. These DNAs can be obtained by using a method for chemical synthesis, a method for cDNA cloning and the like.
  • the cDNAs of the present invention can be cloned, for example, from cDNA libraries derived from the human cells.
  • the cDNAs are synthesized by using poly(A) + RNAs extracted from human cells as templates.
  • the human cells may be cells delivered from the human body, for example, by the operation or may be the cultured cells.
  • the cDNAs can be synthesized by using any method such as the Okayama-Berg method [Okayama, H. and Berg, P., Mol. Cell. Biol. 2: 161-170 (1982)], the Gubler-Hoffman method [Gubler, U. and Hoffman, J., Gene 25: 263-269 (1983)] and the like.
  • cDNAs of the present invention can be cloned from the cDNA libraries by synthesizing an oligonucleotide on the basis of base sequences of any portion in the cDNA of the present invention and screening the cDNA libraries using this oligonucleotide as a probe for colony or plaque hybridization according to a method known in the art.
  • the cDNA fragments of the present invention can be prepared from an mRNA isolated from human cells by the RT- PCR method in which oligonucleotides which hybridize with both termini of the cDNA fragment of interest are synthesized, which are then used as the primers.
  • the cDNAs of the present invention are characterized in that they comprise any one of the base sequences represented by SEQ ID NOS: 11 to 20, 41 to 50, 71 to 80, 101 to 110, and 131 to 140 or the base sequences represented by SEQ ID NOS: 21 to 30, 51 to 60, 81 to 90, 111 to 120, and 141 to 150.
  • Table 1 summarizes the clone number (HP number), the cells from which the cDNA clone was obtained, the total base number of the cDNA, and the number of the amino acid residues of the encoded protein, for each of the cDNAs.
  • the same clones as the cDNAs of the present invention can be easily obtained by screening the cDNA libraries constructed from the human cell lines or human tissues utilized in the present invention using an oligonucleotide probe synthesized on the basis of the base sequence of the cDNA provided in any one of SEQ ID NOS: 11 to 30, 41 to 60, 71 to 90, 101 to 120, and 131 to 150.
  • any cDNA in which one or plural nucleotides are added, deleted and/or substituted with other nucleotides in SEQ ID NOS: 11 to 30, 41 to 60, 71 to 90, 101 to 120, and 131 to 150 shall come within the scope of the present invention.
  • any protein in which one or plural amino acids are added, deleted and/or substituted with other amino acids resulting from the above-mentioned changes shall come within the scope of the present invention, as long as the protein possesses the activity of the protein having any one of the amino acid sequences represented by SEQ ID NOS: 1 to 10, 31 to 40, 61 to 70, 91 to 100, and 121 to 130.
  • the cDNAs of the present invention also include cDNA fragments (of 10 bp or more) containing any partial base sequence in the base sequences represented by SEQ ID NOS: 11 to 20, 41 to 50, 71 to 80, 101 to 110, and 131 to 140 or in the base sequences represented by SEQ ID NOS: 21 to 30, 51 to 60, 81 to 90, 111 to 120, and 141 to 150.
  • DNA fragments consisting of a sense strand and an anti-sense strand shall come within this scope. These DNA fragments can be utilized as the probes for the genetic diagnosis.
  • polynucleotides and proteins of the present invention may exhibit one or more of the uses or biological activities (including those associated with assays cited herein) identified below.
  • Uses or activities described for proteins of the present invention may be provided by administration or use of such proteins or by administration or use of polynucleotides encoding such proteins (such as, for example, in gene therapies or vectors suitable for introduction of DNA).
  • the polynucleotides provided by the present invention can be used by the research community for various purposes.
  • the polynucleotides can be used to express recombinant protein for analysis, characterization or therapeutic use; as markers for tissues in which the corresponding protein is preferentially expressed (either constitutively or at a particular stage of tissue differentiation or development or in disease states ) ; as molecular weight markers on Southern gels; as chromosome markers or tags (when labeled) to identify chromosomes or to map related gene positions; to compare with endogenous DNA sequences in patients to identify potential genetic disorders; as probes to hybridize and thus discover novel, related DNA sequences; as a source of information to derive PCR primers for genetic fingerprinting; as a probe to "subtract-out" known sequences in the process of discovering other novel polynucleotides; for selecting and making oligomers for attachment to a "gene chip” or other support, including for examination of expression patterns; to raise anti-protein antibodies using DNA immun
  • the polynucleotide encodes a protein which binds or potentially binds to another protein (such as, for example, in a receptor-ligand interaction)
  • the polynucleotide can also be used in interaction trap assays (such as, for example, that described in Gyuris et al., Cell 75:791-803 (1993)) to identify polynucleotides encoding the other protein with which binding occurs or to identify inhibitors of the binding interaction.
  • the proteins provided by the present invention can similarly be used in assay to determine biological activity, including in a panel of multiple proteins for high- throughput screening; to raise antibodies or to elicit another immune response; as a reagent (including the labeled reagent) in assays designed to quantitatively determine levels of the protein (or its receptor) in biological fluids; as markers for tissues in which the corresponding protein is preferentially expressed (either constitutively or at a particular stage of tissue differentiation or development or in a disease state); and, of course, to isolate correlative receptors or ligands.
  • the protein binds or potentially binds to another protein (such as, for example, in a receptor-ligand interaction)
  • the protein can be used to identify the other protein with which binding occurs or to identify inhibitors of the binding interaction. Proteins involved in these binding interactions can also be used to screen for peptide or small molecule inhibitors or agonists of the binding interaction.
  • Polynucleotides and proteins of the present invention can also be used as nutritional sources or supplements. Such uses include without limitation use as a protein or amino acid supplement, use as a carbon source, use as a nitrogen source and use as a source of carbohydrate.
  • the protein or polynucleotide of the invention can be added to the feed of a particular organism or can be administered as a separate solid or liquid preparation, such as in the form of powder, pills, solutions, suspensions or capsules.
  • the protein or polynucleotide of the invention can be added to the medium in or on which the microorganism is cultured. Cytokine and Cell Proliferation/Differentiation Activity
  • a protein of the present invention may exhibit cytokine, cell proliferation (either inducing or inhibiting) or cell differentiation (either inducing or inhibiting) activity or may induce production of other cytokines in certain cell populations.
  • cytokine cytokine
  • cell proliferation either inducing or inhibiting
  • cell differentiation either inducing or inhibiting
  • the activity of a protein of the present invention is evidenced by any one of a number of routine factor dependent cell proliferation assays for cell lines including, without limitation, 32D, DA2, DA1G, T10, B9, B9/11, BaF3, MC9/G, M+ (preB M+) , 2E8, RB5, DAI, 123, T1165, HT2, CTLL2, TF-1, Mo7e and CMK.
  • the activity of a protein of the invention may, among other means, be measured by the following methods:
  • Assays for T-cell or thymocyte proliferation include without limitation those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A.M. Kruisbeek, D.H. Margulies, E.M. Shevach, W Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 3, In Vitro assays for Mouse Lymphocyte Function 3.1-3.19; Chapter 7, Immunologic studies in Humans); Takai et al., J. Immunol. 137:3494-3500, 1986; Bertagnolli et al., J. Immunol.
  • Assays for cytokine production and/or proliferation of spleen cells, lymph node cells or thymocytes include, without limitation, those described in: Polyclonal T cell stimulation, Kruisbeek, A.M. and Shevach, E.M. In Current Protocols in Immunology. J.E.e.a. Coligan eds. Vol 1 pp. 3.12.1-3.12.14, John Wiley and Sons, Toronto. 1994; and Measurement of mouse and human Interferon ⁇ , Schreiber, R.D. In Current Protocols in Immunology. J.E.e.a. Coligan eds. Vol 1 pp. 6.8.1-6.8.8, John Wiley and Sons, Toronto. 1994.
  • Assays for proliferation and differentiation of hematopoietic and lymphopoietic cells include, without limitation, those described in: Measurement of Human and Murine Interleukin 2 and Interleukin 4, Bottomly, K., Davis, L.S. and Lipsky, P.E. In Current Protocols in Immunology. J.E.e.a. Coligan eds. Vol 1 pp. 6.3.1-6.3.12, John Wiley and Sons, Toronto. 1991; deVries et al., J. Exp. Med. 173:1205- 1211, 1991; Moreau et al., Nature 336:690-692, 1988; Greenberger et al., Proc. Natl. Acad. Sci. U.S.A.
  • a protein of the present invention may also exhibit immune stimulating or immune suppressing activity, including without limitation the activities for which assays are described herein.
  • a protein may be useful in the treatment of various immune deficiencies and disorders (including severe combined immunodeficiency (SCID)), e.g., in regulating (up or down) growth and proliferation of T and/or B lymphocytes, as well as effecting the cytolytic activity of NK cells and other cell populations.
  • SCID severe combined immunodeficiency
  • These immune deficiencies may be genetic or be caused by viral (e.g., HIV) as well as bacterial or fungal infections, or may result from autoimmune disorders.
  • infectious diseases causes by viral, bacterial, fungal or other infection may be treatable using a protein of the present invention, including infections by HIV, hepatitis viruses, herpesviruses, mycobacteria, Leishmania spp., malaria spp. and various fungal infections such as candidiasis.
  • a protein of the present invention may also be useful where a boost to the immune system generally may be desirable, i.e., in the treatment of cancer.
  • Autoimmune disorders which may be treated using a protein of the present invention include, for example, connective tissue disease, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, autoimmune pulmonary inflammation, Guillain-Barre syndrome, autoimmune thyroiditis, insulin dependent diabetes mellitis, myasthenia gravis, graft-versus-host disease and autoimmune inflammatory eye disease.
  • a protein of the present invention may also to be useful in the treatment of allergic reactions and conditions, such as asthma (particularly allergic asthma) or other respiratory problems.
  • Other conditions, in which immune suppression is desired may also be treatable using a protein of the present invention.
  • T cells may be inhibited by suppressing T cell responses or by inducing specific tolerance in T cells, or both.
  • Immunosuppression of T cell responses is generally an active, non-antigen-specific, process which requires continuous exposure of the T cells to the suppressive agent.
  • Tolerance which involves inducing non-responsiveness or anergy in T cells, is distinguishable from immunosuppression in that it is generally antigen- specific and persists after exposure to the tolerizing agent has ceased. Operationally, tolerance can be demonstrated by the lack of a T cell response upon reexposure to specific antigen in the absence of the tolerizing agent.
  • Down regulating or preventing one or more antigen functions (including without limitation B lymphocyte antigen functions (such as , for example, B7)), e.g., preventing high level lymphokine synthesis by activated T cells, will be useful in situations of tissue, skin and organ transplantation and in graft-versus-host disease (GVHD) .
  • B lymphocyte antigen functions such as , for example, B7
  • GVHD graft-versus-host disease
  • a molecule which inhibits or blocks interaction of a B7 lymphocyte antigen with its natural ligand(s) on immune cells such as a soluble, monomeric form of a peptide having B7-2 activity alone or in conjunction with a monomeric form of a peptide having an activity of another B lymphocyte antigen (e.g., B7-1, B7-3) or blocking antibody
  • B7 lymphocyte antigen e.g., B7-1, B7-3 or blocking antibody
  • Blocking B lymphocyte antigen function in this matter prevents cytokine synthesis by immune cells, such as T cells, and thus acts as an immunosuppressant.
  • the lack of costimulation may also be sufficient to anergize the T cells, thereby inducing tolerance in a subject.
  • Induction of long-term tolerance by B lymphocyte antigen-blocking reagents may avoid the necessity of repeated administration of these blocking reagents.
  • the efficacy of particular blocking reagents in preventing organ transplant rejection or GVHD can be assessed using animal models that are predictive of efficacy in humans.
  • appropriate systems which can be used include allogeneic cardiac grafts in rats and xenogeneic pancreatic islet cell grafts in mice, both of which have been used to examine the immunosuppressive effects of CTLA4Ig fusion proteins in vivo as described in Lenschow et al., Science 257:789-792 (1992) and Turka et al., Proc. Natl. Acad. Sci USA, 89:11102-11105 (1992).
  • murine models of GVHD see Paul ed., Fundamental Immunology, Raven Press, New York, 1989, pp. 846-847) can be used to determine the effect of blocking B lymphocyte antigen function in vivo on the development of that disease.
  • Blocking antigen function may also be therapeutically useful for treating autoimmune diseases.
  • Many autoimmune disorders are the result of inappropriate activation of T cells that are reactive against self tissue and which promote the production of cytokines and autoantibodies involved in the pathology of the diseases.
  • Preventing the activation of autoreactive T cells may reduce or eliminate disease symptoms.
  • Administration of reagents which block costimulation of T cells by disrupting receptor :ligand interactions of B lymphocyte antigens can be used to inhibit T cell activation and prevent production of autoantibodies or T cell-derived cytokines which may be involved in the disease process.
  • blocking reagents may induce antigen-specific tolerance of autoreactive T cells which could lead to long-term relief from the disease.
  • the efficacy of blocking reagents in preventing or alleviating autoimmune disorders can be determined using a number of well-characterized animal models of human autoimmune diseases. Examples include murine experimental autoimmune encephalitis, systemic lupus erythmatosis in MRL/lpr/lpr mice or NZB hybrid mice, murine autoimmune collagen arthritis, diabetes mellitus in NOD mice and BB rats, and murine experimental myasthenia gravis (see Paul ed., Fundamental Immunology, Raven Press, New York, 1989, pp. 840-856). Upregulation of an antigen function (preferably a B lymphocyte antigen function) , as a means of up regulating immune responses, may also be useful in therapy.
  • an antigen function preferably a B lymphocyte antigen function
  • Upregulation of immune responses may be in the form of enhancing an existing immune response or eliciting an initial immune response.
  • enhancing an immune response through stimulating B lymphocyte antigen function may be useful in cases of viral infection.
  • systemic viral diseases such as influenza, the common cold, and encephalitis might be alleviated by the administration of stimulatory forms of B lymphocyte antigens systemically.
  • anti-viral immune responses may be enhanced in an infected patient by removing T cells from the patient, costimulating the T cells in vitro with viral antigen-pulsed APCs either expressing a peptide of the present invention or together with a stimulatory form of a soluble peptide of the present invention and reintroducing the in vitro activated T cells into the patient.
  • Another method of enhancing anti-viral immune responses would be to isolate infected cells from a patient, transfect them with a nucleic acid encoding a protein of the present invention as described herein such that the cells express all or a portion of the protein on their surface, and reintroduce the transfected cells into the patient.
  • the infected cells would now be capable of delivering a costimulatory signal to, and thereby activate, T cells in vivo.
  • up regulation or enhancement of antigen function may be useful in the induction of tumor immunity.
  • Tumor cells e.g., sarcoma, melanoma, lymphoma, leukemia, neuroblastoma, carcinoma
  • a nucleic acid encoding at least one peptide of the present invention can be administered to a subject to overcome tumor-specific tolerance in the subject. If desired, the tumor cell can be transfected to express a combination of peptides.
  • tumor cells obtained from a patient can be transfected ex vivo with an expression vector directing the expression of a peptide having B7-2-like activity alone, or in conjunction with a peptide having B7-l-like activity and/or B7-3-like activity.
  • the transfected tumor cells are returned to the patient to result in expression of the peptides on the surface of the transfected cell.
  • gene therapy techniques can be used to target a tumor cell for transfection in vivo.
  • tumor cells which lack MHC class I or MHC class II molecules, or which fail to reexpress sufficient amounts of MHC class I or MHC class II molecules, can be transfected with nucleic acid encoding all or a portion of (e.g., a cytoplasmic-domain truncated portion) of an MHC class I ⁇ chain protein and ⁇ 2 microglobulin protein or an MHC class II chain protein and an MHC class II /3 chain protein to thereby express MHC class I or MHC class II proteins on the cell surface.
  • nucleic acid encoding all or a portion of (e.g., a cytoplasmic-domain truncated portion) of an MHC class I ⁇ chain protein and ⁇ 2 microglobulin protein or an MHC class II chain protein and an MHC class II /3 chain protein to thereby express MHC class I or MHC class II proteins on the cell surface.
  • a gene encoding an antisense construct which blocks expression of an MHC class II associated protein, such as the invariant chain can also be cotransfected with a DNA encoding a peptide having the activity of a B lymphocyte antigen to promote presentation of tumor associated antigens and induce tumor specific immunity.
  • a T cell mediated immune response in a human subject may be sufficient to overcome tumor-specific tolerance in the subject.
  • the activity of a protein of the invention may, among other means, be measured by the following methods:
  • Suitable assays for thymocyte or splenocyte cytotoxicity include, without limitation, those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A.M. Kruisbeek, D.H. Margulies, E.M. Shevach, W Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 3, In Vitro assays for Mouse Lymphocyte Function 3.1-3.19; Chapter 7, Immunologic studies in Humans) ; Herrmann et al. , Proc. Natl. Acad. Sci. USA 78:2488-2492, 1981; Herrmann et al., J. Immunol. 128:1968-1974, 1982; Handa et al., J. Immunol.
  • T-cell-dependent immunoglobulin responses and isotype switching (which will identify, among others, proteins that modulate T-cell dependent antibody responses and that affect Thl/Th2 profiles) include, without limitation, those described in: Maliszewski, J. Immunol. 144:3028-3033, 1990; and Assays for B cell function: In vitro antibody production, Mond, J.J. and Brunswick, M. In Current Protocols in Immunology. J.E.e.a. Coligan eds. Vol 1 pp. 3.8.1-3.8.16, John Wiley and Sons, Toronto. 1994.
  • MLR Mixed lymphocyte reaction
  • Dendritic cell-dependent assays (which will identify, among others, proteins expressed by dendritic cells that activate naive T-cells) include, without limitation, those described in: Guery et al., J. Immunol. 134:536-544, 1995; Inaba et al., Journal of Experimental Medicine 173:549-559, 1991; Macatonia et al., Journal of Immunology 154:5071-5079, 1995; Porgador et al., Journal of Experimental Medicine 182:255-260, 1995; Nair et al., Journal of Virology 67:4062- 4069, 1993; Huang et al., Science 264:961-965, 1994; Macatonia et al., Journal of Experimental Medicine 169:1255- 1264, 1989; Bhardwaj et al., Journal of Clinical Investigation 94:797-807, 1994; and Inaba et al., Journal of Experimental Medicine 172:631-640, 1990.
  • lymphocyte survival/apoptosis (which will identify, among others, proteins that prevent apoptosis after superantigen induction and proteins that regulate lymphocyte homeostasis) include, without limitation, those described in: Darzynkiewicz et al., Cytometry 13:795-808, 1992; Gorczyca et al., Leukemia 7:659-670, 1993; Gorczyca et al., Cancer Research 53:1945-1951, 1993; Itoh et al., Cell 66:233-243, 1991; Zacharchuk, Journal of Immunology 145:4037-4045, 1990; Zamai et al., Cytometry 14:891-897, 1993; Gorczyca et al., International Journal of Oncology 1:639-648, 1992.
  • Assays for proteins that influence early steps of T- cell commitment and development include, without limitation, those described in: Antica et al., Blood 84:111-117, 1994; Fine et al., Cellular Immunology 155:111-122, 1994; Galy et al., Blood 85:2770-2778, 1995; Toki et al., Proc. Nat. Acad Sci. USA 88:7548-7551, 1991.
  • a protein of the present invention may be useful in regulation of hematopoiesis and, consequently, in the treatment of myeloid or lymphoid cell deficiencies. Even marginal biological activity in support of colony forming cells or of factor-dependent cell lines indicates involvement in regulating hematopoiesis, e.g.
  • erythroid progenitor cells in supporting the growth and proliferation of erythroid progenitor cells alone or in combination with other cytokines, thereby indicating utility, for example, in treating various anemias or for use in conjunction with irradiation/chemotherapy to stimulate the production of erythroid precursors and/or erythroid cells; in supporting the growth and proliferation of myeloid cells such as granulocytes and monocytes/macrophages (i.e., traditional CSF activity) useful, for example, in conjunction with chemotherapy to prevent or treat consequent myelo-suppression; in supporting the growth and proliferation of megakaryocytes and consequently of platelets thereby allowing prevention or treatment of various platelet disorders such as thro bocytopenia, and generally for use in place of or complementary to platelet transfusions; and/or in supporting the growth and proliferation of hematopoietic stem cells which are capable of maturing to any and all of the above- mentioned hematopoietic cells and therefore find therapeutic utility in various stem cell disorders
  • the activity of a protein of the invention may, among other means, be measured by the following methods:
  • Assays for embryonic stem cell differentiation include, without limitation, those described in: Johansson et al. Cellular Biology 15:141-151, 1995; Keller et al., Molecular and Cellular Biology 13:473-486, 1993; McClanahan et al., Blood 81:2903-2915, 1993.
  • Assays for stem cell survival and differentiation include, without limitation, those described in: Methylcellulose colony forming assays, Freshney, M.G. In Culture of Hematopoietic Cells. R.I. Freshney, et al. eds. Vol pp. 265-268, Wiley-Liss, Inc., New York, NY. 1994; Hirayama et al., Proc. Natl. Acad. Sci. USA 89:5907-5911, 1992; Primitive hematopoietic colony forming cells with high proliferative potential, McNiece, I.K. and Briddell, R.A.
  • a protein of the present invention also may have utility in compositions used for bone, cartilage, tendon, ligament and/or nerve tissue growth or regeneration, as well as for wound healing and tissue repair and replacement, and in the treatment of burns, incisions and ulcers.
  • a protein of the present invention which induces cartilage and/or bone growth in circumstances where bone is not normally formed, has application in the healing of bone fractures and cartilage damage or defects in humans and other animals.
  • Such a preparation employing a protein of the invention may have prophylactic use in closed as well as open fracture reduction and also in the improved fixation of artificial joints.
  • De novo bone formation induced by an osteogenic agent contributes to the repair of congenital, trauma induced, or oncologic resection induced craniofacial defects, and also is useful in cosmetic plastic surgery.
  • a protein of this invention may also be used in the treatment of periodontal disease, and in other tooth repair processes.
  • Such agents may provide an environment to attract bone-forming cells, stimulate growth of bone-forming cells or induce differentiation of progenitors of bone-forming cells.
  • a protein of the invention may also be useful in the treatment of osteoporosis or osteoarthritis, such as through stimulation of bone and/or cartilage repair or by blocking inflammation or processes of tissue destruction (collagenase activity, osteoclast activity, etc.) mediated by inflammatory processes.
  • tissue regeneration activity that may be attributable to the protein of the present invention is tendon/ligament formation.
  • a protein of the present invention which induces tendon/ligament-like tissue or other tissue formation in circumstances where such tissue is not normally formed, has application in the healing of tendon or ligament tears, deformities and other tendon or ligament defects in humans and other animals.
  • Such a preparation employing a tendon/ligament-like tissue inducing protein may have prophylactic use in preventing damage to tendon or ligament tissue, as well as use in the improved fixation of tendon or ligament to bone or other tissues, and in repairing defects to tendon or ligament tissue.
  • compositions of the present invention contributes to the repair of congenital, trauma induced, or other tendon or ligament defects of other origin, and is also useful in cosmetic plastic surgery for attachment or repair of tendons or ligaments.
  • the compositions of the present invention may provide an environment to attract tendon or ligament-forming cells, stimulate growth of tendon- or ligament-forming cells, induce differentiation of progenitors of tendon- or ligament-forming cells, or induce growth of tendon/ligament cells or progenitors ex vivo for return in vivo to effect tissue repair.
  • the compositions of the invention may also be useful in the treatment of tendinitis, carpal tunnel syndrome and other tendon or ligament defects.
  • the compositions may also include an appropriate matrix and/or sequestering agent as a carrier as is well known in the art.
  • the protein of the present invention may also be useful for proliferation of neural cells and for regeneration of nerve and brain tissue, i.e. for the treatment of central and peripheral nervous system diseases and neuropathies, as well as mechanical and traumatic disorders, which involve degeneration, death or trauma to neural cells or nerve tissue. More specifically, a protein may be used in the treatment of diseases of the peripheral nervous system, such as peripheral nerve injuries, peripheral neuropathy and localized neuropathies, and central nervous system diseases, such as Alzheimer's, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Shy-Drager syndrome. Further conditions which may be treated in accordance with the present invention include mechanical and traumatic disorders, such as spinal cord disorders, head trauma and cerebrovascular diseases such as stroke.
  • Proteins of the invention may also be useful to promote better or faster closure of non-healing wounds, including without limitation pressure ulcers, ulcers associated with vascular insufficiency, surgical and traumatic wounds and the like. It is expected that a protein of the present invention may also exhibit activity for generation or regeneration of other tissues, such as organs (including, for example, pancreas, liver, intestine, kidney, skin, endothelium) , muscle (smooth, skeletal or cardiac) and vascular (including vascular endothelium) tissue, or for promoting the growth of cells comprising such tissues.
  • organs including, for example, pancreas, liver, intestine, kidney, skin, endothelium
  • muscle smooth, skeletal or cardiac
  • vascular including vascular endothelium
  • Part of the desired effects may be by inhibition or modulation of fibrotic scarring to allow normal tissue to regenerate.
  • a protein of the invention may also exhibit angiogenic activity.
  • a protein of the present invention may also be useful for gut protection or regeneration and treatment of lung or liver fibrosis, reperfusion injury in various tissues, and conditions resulting from systemic cytokine damage.
  • a protein of the present invention may also be useful for promoting or inhibiting differentiation of tissues described above from precursor tissues or cells; or for inhibiting the growth of tissues described above.
  • tissue generation activity include, without limitation, those described in: International Patent Publication No. WO95/16035 (bone, cartilage, tendon); International Patent Publication No. WO95/05846 (nerve, neuronal); International Patent Publication No. WO91/07491 (skin, endothelium ).
  • Assays for wound healing activity include, without limitation, those described in: Winter, Epidermal Wound
  • a protein of the present invention may also exhibit activin- or inhibin-related activities. Inhibins are characterized by their ability to inhibit the release of follicle stimulating hormone (FSH), while activins and are characterized by their ability to stimulate the release of follicle stimulating hormone (FSH) .
  • FSH follicle stimulating hormone
  • a protein of the present invention alone or in heterodimers with a member of the inhibin family, may be useful as a contraceptive based on the ability of inhibins to decrease fertility in female mammals and decrease spermatogenesis in male mammals. Administration of sufficient amounts of other inhibins can induce infertility in these mammals.
  • the protein of the invention may be useful as a fertility inducing therapeutic, based upon the ability of activin molecules in stimulating FSH release from cells of the anterior pituitary. See, for example, United States Patent 4,798,885.
  • a protein of the invention may also be useful for advancement of the onset of fertility in sexually immature mammals, so as to increase the lifetime reproductive performance of domestic animals such as cows, sheep and pigs.
  • the activity of a protein of the invention may, among other means, be measured by the following methods:
  • Assays for activin/inhibin activity include, without limitation, those described in: Vale et al., Endocrinology 91:562-572, 1972; Ling et al., Nature 321:779-782, 1986; Vale et al., Nature 321:776-779, 1986; Mason et al., Nature 318:659-663, 1985; Forage et al., Proc. Natl. Acad. Sci. USA 83:3091-3095, 1986.
  • a protein of the present invention may have chemotactic or chemokinetic activity (e.g., act as a chemokine) for mammalian cells, including, for example, monocytes, fibroblasts, neutrophils, T-cells, mast cells, eosinophils, epithelial and/or endothelial cells.
  • Chemotactic and chemokinetic proteins can be used to mobilize or attract a desired cell population to a desired site of action.
  • Chemotactic or chemokinetic proteins provide particular advantages in treatment of wounds and other trauma to tissues, as well as in treatment of localized infections. For example, attraction of lymphocytes, monocytes or neutrophils to tumors or sites of infection may result in improved immune responses against the tumor or infecting agent.
  • a protein or peptide has chemotactic activity for a particular cell population if it can stimulate, directly or indirectly, the directed orientation or movement of such cell population.
  • the protein or peptide has the ability to directly stimulate directed movement of cells. Whether a particular protein has chemotactic activity for a population of cells can be readily determined by employing such protein or peptide in any known assay for cell chemotaxis .
  • the activity of a protein of the invention may, among other means, be measured by the following methods:
  • Assays for chemotactic activity consist of assays that measure the ability of a protein to induce the migration of cells across a membrane as well as the ability of a protein to induce the adhesion of one cell population to another cell population.
  • Suitable assays for movement and adhesion include, without limitation, those described in: Current Protocols in Immunology, Ed by J.E. Coligan, A.M. Kruisbeek, D.H. Margulies, E.M. Shevach, W.Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 6.12, Measurement of alpha and beta Chemokines 6.12.1- 6.12.28; Taub et al. J. Clin. Invest.
  • a protein of the invention may also exhibit hemostatic or thrombolytic activity. As a result, such a protein is expected to be useful in treatment of various coagulation disorders (including hereditary disorders, such as hemophilias) or to enhance coagulation and other hemostatic events in treating wounds resulting from trauma, surgery or other causes.
  • a protein of the invention may also be useful for dissolving or inhibiting formation of thromboses and for treatment and prevention of conditions resulting therefrom (such as, for example, infarction of cardiac and central nervous system vessels (e.g., stroke)).
  • the activity of a protein of the invention may, among other means, be measured by the following methods:
  • Assay for hemostatic and thrombolytic activity include, without limitation, those described in: Linet et al., J. Clin. Pharmacol. 26:131-140, 1986; Burdick et al., Thrombosis Res. 45:413-419, 1987; Humphrey et al., Fibrinolysis 5:71-79 (1991); Schaub, Prostaglandins 35:467- 474, 1988.
  • a protein of the present invention may also demonstrate activity as receptors, receptor ligands or inhibitors or agonists of receptor/ligand interactions.
  • receptors and ligands include, without limitation, cytokine receptors and their ligands, receptor kinases and their ligands, receptor phosphatases and their ligands, receptors involved in cell-cell interactions and their ligands (including without limitation, cellular adhesion molecules (such as selectins, integrins and their ligands) and receptor/ligand pairs involved in antigen presentation, antigen recognition and development of cellular and humoral immune responses) .
  • Receptors and ligands are also useful for screening of potential peptide or small molecule inhibitors of the relevant receptor/ligand interaction.
  • a protein of the present invention may themselves be useful as inhibitors of receptor/ligand interactions.
  • the activity of a protein of the invention may, among other means, be measured by the following methods:
  • Suitable assays for receptor-ligand activity include without limitation those described in: Current Protocols in Immunology, Ed by J.E. Coligan, A.M. Kruisbeek, D.H. Margulies, E.M. Shevach, W.Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 7.28, Measurement of Cellular Adhesion under static conditions 7.28.1-7.28.22), Takai et al., Proc. Natl. Acad. Sci. USA 84:6864-6868, 1987; Bierer et al., J. Exp. Med. 168:1145-1156, 1988; Rosenstein et al., J. Exp. Med. 169:149-160 1989; Stoltenborg et al., J. Immunol. Methods 175:59-68, 1994; Stitt et al., Cell 80:661-670, 1995. Anti-Inflammatory Activity
  • Proteins of the present invention may also exhibit anti-inflammatory activity.
  • the anti-inflammatory activity may be achieved by providing a stimulus to cells involved in the inflammatory response, by inhibiting or promoting cell- cell interactions (such as, for example, cell adhesion), by inhibiting or promoting chemotaxis of cells involved in the inflammatory process, inhibiting or promoting cell extravasation, or by stimulating or suppressing production of other factors which more directly inhibit or promote an inflammatory response.
  • Proteins exhibiting such activities can be used to treat inflammatory conditions including chronic or acute conditions) , including without limitation inflammation associated with infection (such as septic shock, sepsis or systemic inflammatory response syndrome (SIRS)), ischemia-reperfusion injury, endotoxin lethality, arthritis, complement-mediated hyperacute rejection, nephritis, cytokine or chemokine-induced lung injury, inflammatory bowel disease, Crohn's disease or resulting from over production of cytokines such as TNF or IL-1. Proteins of the invention may also be useful to treat anaphylaxis and hypersensitivity to an antigenic substance or material.
  • infection such as septic shock, sepsis or systemic inflammatory response syndrome (SIRS)
  • ischemia-reperfusion injury such as endotoxin lethality, arthritis, complement-mediated hyperacute rejection, nephritis, cytokine or chemokine-induced lung injury, inflammatory bowel disease, Crohn's disease or
  • a protein of the invention may exhibit other anti-tumor activities.
  • a protein may inhibit tumor growth directly or indirectly (such as, for example, via ADCC) .
  • a protein may exhibit its tumor inhibitory activity by acting on tumor tissue or tumor precursor tissue, by inhibiting formation of tissues necessary to support tumor growth (such as, for example, by inhibiting angiogenesis), by causing production of other factors, agents or cell types which inhibit tumor growth, or by suppressing, eliminating or inhibiting factors, agents or cell types which promote tumor growth.
  • a protein of the invention may also exhibit one or more of the following additional activities or effects: inhibiting the growth, infection or function of, or killing, infectious agents, including, without limitation, bacteria, viruses, fungi and other parasites; effecting (suppressing or enhancing) bodily characteristics, including, without limitation, height, weight, hair color, eye color, skin, fat to lean ratio or other tissue pigmentation, or organ or body part size or shape (such as, for example, breast augmentation or diminution, change in bone form or shape); effecting biorhythms or caricadic cycles or rhythms; effecting the fertility of male or female subjects; effecting the metabolism, catabolism, anabolism, processing, utilization, storage or elimination of dietary fat, lipid, protein, carbohydrate, vitamins, minerals, cofactors or other nutritional factors or component( s) ; effecting behavioral characteristics, including, without limitation, appetite, libido, stress, cognition (including cognitive disorders), depression (including depressive disorders) and violent behaviors; providing analgesic effects or other pain reducing effects;
  • the cDNA library of osteosarcoma cell line Saos-2 (WO 97/33993)
  • the cDNA library of epidermoid carcinoma cell line KB (WO 98/11217)
  • the cDNA library of liver tissue delivered by the operation (WO 98/21328) were used as the cDNA libraries.
  • the cDNA libraries constructed from phorbol ester-stimulated histiocytic lymphoma cell line U937 (ATCC CRL 1593) mRNA, human retinoblastoma cell line WERI-RB (ATCC HTB 169) mRNA and human thymus mRNA (Clontech) were also used.
  • Full-length cDNA clones were selected from the respective libraries and the whole base sequences thereof were determined to construct a homo-protein cDNA bank consisting of the full-length cDNA clones.
  • the hydrophobicity/hydrophilicity profiles were determined for the proteins encoded by the full-length cDNA clones registered in the homo-protein cDNA bank by the Kyte- Doolittle method [Kyte, J. & Doolittle, R. F., J. Mol. Biol. 157: 105-132 (1982)] to examine the presence or absence of a hydrophobic region.
  • a clone that has a hydrophobic region being assumed as a secretory signal or a transmembrane domain in the amino acid sequence of the encoded protein was selected as a clone candidate.
  • the plasmid vector bearing the cDNA of the present invention was used for in vitro transcription/translation with a T N T rabbit reticulocyte lysate kit (Promega).
  • a T N T rabbit reticulocyte lysate kit Promega.
  • [ 3S S]methionine was added to label the expression product with a radioisotope.
  • Each of the reactions was carried out according to the protocols attached to the kit.
  • Two micrograms of the plasmid was subjected to the reaction at 30°C for 90 minutes in the reaction solution of a total volume of 25 ⁇ l containing 12.5 ⁇ l ⁇ of T H T rabbit reticulocyte lysate, 0.5 ⁇ l of a buffer solution (attached to the kit), 2 ⁇ l of an amino acid mixture (without methionine), 2 ⁇ l of [ 35 S]methionine (Amersham) (0.37 MBq/ ⁇ l), 0.5 ⁇ l of T7 RNA polymerase, and 20 U of RNasin.
  • the experiment in the presence of a membrane system was carried out by adding 2.5 ⁇ l of a canine pancreas microsome fraction (Promega) to the reaction system.
  • Escherichia coli cells harboring the expression vector for the protein of the present invention were cultured at 37°C for 2 hours in 2 ml of the 2xYT culture medium containing 100 ⁇ g/ml of ampicillin, the helper phage M13K07 (50 ⁇ l) was added, and the cells were then cultured at 37°C overnight.
  • Single-stranded phage particles were obtained by polyethylene glycol precipitation from a supernatant separated by centrifugation. The particles were suspended in 100 ⁇ l of 1 mM Tris-0.1 mM EDTA, pH 8 (TE) .
  • the cultured cells derived from monkey kidney, COS7 were cultured at 37°C in the presence of 5% C0 2 in the Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal calf serum. 1 x 10 5 COS7 cells were inoculated into a 6-well plate (Nunc, well diameter: 3 cm) and cultured at 37°C for 22 hours in the presence of 5% C0 2 . After the medium was removed, the cell surface was washed with a phosphate buffer solution followed by DMEM containing 50 mM Tris-hydrochloride (pH 7.5) (TDMEM) .
  • DMEM Dulbecco's modified Eagle's medium
  • Determination of the whole base sequence of the cDNA insert of clone HP02770 obtained from cDNA library of human fibrosarcoma cell line HT-1080 revealed the structure consisting of a 252-bp 5 '-untranslated region, a 1053-bp ORF, and a 204-bp 3 '-untranslated region.
  • the ORF encodes a protein consisting of 350 amino acid residues and there existed two putative transmembrane domains.
  • Figure 2 depicts the hydrophobicity/hydrophilicity profile, obtained by the Kyte-Doolittle method, of the present protein. In vitro translation resulted in formation of a translation product of 42 kDa that was somewhat larger than the molecular weight of 38,274 predicted from the ORF.
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. AA434312) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • ⁇ HP02869> (SEQ ID NOS: 3, 13, and 23) Determination of the whole base sequence of the cDNA insert of clone HP02869 obtained from cDNA library of human epidermoid carcinoma cell line KB revealed the structure consisting of a 229-bp 5 ' -untranslated region, a 621-bp ORF, and a 2209-bp 3 '-untranslated region.
  • the ORF encodes a protein consisting of 206 amino acid residues and there existed two putative transmembrane domains.
  • Figure 3 depicts the hydrophobicity/hydrophilicity profile, obtained by the Kyte-Doolittle method, of the present protein. In vitro translation resulted in formation of a translation product of 22 kDa that was almost identical with the molecular weight of 22,367 predicted from the ORF.
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. AA278247) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. T05279) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. T35406) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • ⁇ HP10609> (SEQ ID NOS: 8, 18, and 28) Determination of the whole base sequence of the cDNA insert of clone HP10609 obtained from cDNA library of the human epidermoid carcinoma cell line KB revealed the structure consisting of a 38-bp 5 '-untranslated region, a 735-bp ORF, and a 559-bp 3 ' -untranslated region.
  • the ORF encodes a protein consisting of 244 amino acid residues and there existed one putative transmembrane domain at the N- terminus.
  • Figure 8 depicts the hydrophobicity/hydrophilicity profile, obtained by the Kyte-Doolittle method, of the present protein.
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. T60981) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • the ORF encodes a protein consisting of 303 amino acid residues and there existed a putative secretory signal at the N-terminus.
  • Figure 9 depicts the hydrophobicity/hydrophilicity profile, obtained by the Kyte-Doolittle method, of the present protein. In vitro translation resulted in formation of a translation product of 31 kDa that was somewhat smaller than the molecular weight of 33,856 predicted from the ORF. In this case, the addition of a microsome led to the formation of a product of 36 kDa.
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. H14054) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • ⁇ HP10617> (SEQ ID NOS: 10, 20, and 30) Determination of the whole base sequence of the cDNA insert of clone HP10617 obtained from cDNA library of the human fibrosarcoma cell line HT-1080 revealed the structure consisting of a 72-bp 5 ' -untranslated region, a 483-bp ORF, and a 569-bp 3 ' -untranslated region.
  • the ORF encodes a protein consisting of 160 amino acid residues and there existed four putative transmembrane domains.
  • Figure 10 depicts the hydrophobicity/hydrophilicity profile, obtained by the Kyte-Doolittle method, of the present protein. In vitro translation resulted in formation of a translation product of high molecular weight. When expressed in C0S7 cells, an expression product of about 17 kDa was observed in the membrane fraction.
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. H67672) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • ⁇ HP02837> (SEQ ID NOS: 31, 41, and 51) Determination of the whole base sequence of the cDNA insert of clone HP02837 obtained from cDNA library of human fibrosarcoma cell line HT-1080 revealed the structure consisting of a 44-bp 5 ' -untranslated region, a 4338-bp ORF, and a 91-bp 3 ' -untranslated region.
  • the ORF encodes a protein consisting of 1445 amino acid residues and there existed a putative secretory signal at the N-terminus.
  • Figure 11 depicts the hydrophobicity/hydrophilicity profile, obtained by the Kyte-Doolittle method, of the present protein.
  • HP MQGPPLL TAAHIJLC ⁇ CTAALA-VAPGPRFLVTAPGIIRPGGNVTIGVELLEHCPSQVT
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. W33075) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. AA308536) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • Determination of the whole base sequence of the cDNA insert of clone HP03063 obtained from cDNA library of human fibrosar ⁇ oma cell line HT-1080 revealed the structure consisting of a 88-bp 5 ' -untranslated region, a 1233-bp ORF, and a 151-bp 3 ' -untranslated region.
  • the ORF encodes a protein consisting of 410 amino acid residues and there existed a putative transmembrane domain at the N-terminus.
  • Figure 13 depicts the hydrophobicity/hydrophilicity profile, obtained by the Kyte-Doolittle method, of the present protein. In vitro translation resulted in formation of a translation product of 46 kDa that was almost identical with the molecular weight of 45,786 predicted from the ORF.
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. AA131932) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • ⁇ HP03091> (SEQ ID NOS: 34, 44, and 54) Determination of the whole base sequence of the cDNA insert of clone HP03091 obtained from cDNA library of human liver revealed the structure consisting of a 16-bp 5'- untranslated region, a 1452-bp ORF, and a 184-bp 3'- untranslated region.
  • the ORF encodes a protein consisting of 483 amino acid residues and there existed a putative secretory signal at the N-terminus.
  • Figure 14 depicts the hydrophobicity/hydrophilicity profile, obtained by the Kyte- Doolittle method, of the present protein.
  • Application of the (-3,-1) rule a method for predicting the cleavage site of the secretory signal sequence, allows to expect that the mature protein starts from leucine at position 34.
  • Table 11 shows the comparison between amino acid sequences of the human protein of the present invention (HP) and the human OS-9 protein (OS).
  • HP human protein of the present invention
  • OS human OS-9 protein
  • the marks of -, *, and . represent a gap, an amino acid residue identical with that of the protein of the present invention, and an amino acid residue similar to that of the protein of the present invention, respectively.
  • the both proteins shared a homology of 27.8% in the N-terminal region of 281 amino acid residues.
  • the positions of eight cysteines were conserved between the two proteins.
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. AA313678) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • GenBank Furthermore, the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. AI016020) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • Determination of the whole base sequence of the cDNA insert of clone HP03116 obtained from cDNA library of human epidermoid carcinoma cell line KB revealed the structure consisting of a 32-bp 5 '-untranslated region, a 945-bp ORF, and a 110-bp 3 '-untranslated region.
  • the ORF encodes a protein consisting of 314 amino acid residues and there existed a putative secretory signal at the N-terminus.
  • Figure 16 depicts the hydrophobicity/hydrophilicity profile, obtained by the Kyte-Doolittle method, of the present protein.
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. AA159101) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • ⁇ HP10618> (SEQ ID NOS: 37, 47, and 57) Determination of the whole base sequence of the cDNA insert of clone HP10618 obtained from cDNA library of human fibrosarcoma cell line HT-1080 revealed the structure consisting of a 215-bp 5 ' -untranslated region, a 285-bp ORF, and a 1194-bp 3 '-untranslated region.
  • the ORF encodes a protein consisting of 94 amino acid residues and there existed a putative transmembrane domain at the N-terminus.
  • Figure 17 depicts the hydrophobicity/hydrophilicity profile, obtained by the Kyte-Doolittle method, of the present protein. In vitro translation resulted in formation of a translation product of 10 kDa that was almost identical with the molecular weight of 9,709 predicted from the ORF.
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. AA287125) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • Determination of the whole base sequence of the cDNA insert of clone HP10619 obtained from cDNA library of the human fibrosarcoma cell line HT-1080 revealed the structure consisting of a 11-bp 5 ' -untranslated region, a 657-bp ORF, and a 854-bp 3 '-untranslated region.
  • the ORF encodes a protein consisting of 218 amino acid residues and there existed a putative transmembrane domain at the N-terminus.
  • Figure 18 depicts the hydrophobicity/hydrophilicity profile, obtained by the Kyte-Doolittle method, of the present protein. In vitro translation resulted in formation of a translation product of high molecular weight.
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. Z43089) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • amino acid sequence of this protein there exist in the amino acid sequence of this protein four sites at which N-glycosylation may occur (Asn- Ser-Ser at position 23, Asn-Met-Ser at position 115, Asn- Glu-Thr at position 296 and Asn-Tyr-Thr at position 357).
  • the search of the protein data base using the amino acid sequence of the present protein revealed that the protein was similar to the human angiopoietin-1 (GenBank Accession No. U83508).
  • Table 14 shows the comparison between amino acid sequences of the human protein of the present invention (HP) and the human angiopoietin-1 (AN) . Therein, the marks of -, *, and .
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. R86161) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. R59052) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • ⁇ HP02883> (SEQ ID NOS: 61, 71, and 81) Determination of the whole base sequence of the cDNA insert of clone HP02883 obtained from cDNA library of human epidermoid carcinoma cell line KB revealed the structure consisting of a 191-bp 5 '-untranslated region, a 1179-bp ORF, and a 2657-bp 3 ' -untranslated region.
  • the ORF encodes a protein consisting of 392 amino acid residues and there existed three putative transmembrane domains.
  • Figure 21 depicts the hydrophobicity/hydrophilicity profile, obtained by the Kyte-Doolittle method, of the present protein.
  • CE GKLEEDKKKY-SYLIiKVKYKLKHAIGSTLREVMNNQKRSRRFFFAGGSTCEALHFGCLIS Furthermore, the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. F11409) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • the search of the protein data base using the amino acid sequence of the present protein revealed that the protein was similar to the Caenorhabditis elegans hypothetical protein CELC50D2 (GenBank Accession No. AF040642) .
  • Table 16 shows the comparison between amino acid sequences of the human protein of the present invention (HP) and the Caenorhabditis elegans hypothetical protein CELC50D2 (CE) .
  • the marks of -, *, and . represent a gap, an amino acid residue identical with that of the protein of the present invention, and an amino acid residue similar to that of the protein of the present invention, respectively.
  • the both proteins shared a homology of 37.9% in the N-terminal region of 393 amino acid residues.
  • ⁇ HP10628> (SEQ ID NOS: 63, 73, and 83) Determination of the whole base sequence of the cDNA insert of clone HP10628 obtained from cDNA library of human fibrosarcoma cell line HT-1080 revealed the structure consisting of a 66-bp 5 ' -untranslated region, a 1254-bp ORF, and a 297-bp 3 ' -untranslated region.
  • the ORF encodes a protein consisting of 417 amino acid residues and there existed four putative transmembrane domains.
  • Figure 23 depicts the hydrophobicity/hydrophilicity profile, obtained by the Kyte-Doolittle method, of the present protein. In vitro translation resulted in formation of a translation product of 46 kDa that was almost identical with the molecular weight of 45,461 predicted from the ORF.
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. AA450191) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. AA516481) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • ⁇ HP10636> (SEQ ID NOS: 66, 76, and 86) Determination of the whole base sequence of the cDNA insert of clone HP10636 obtained from cDNA library of human fibrosarcoma cell line HT-1080 revealed the structure consisting of a 179-bp 5 ' -untranslated region, a 1278-bp ORF, and a 255-bp 3 '-untranslated region.
  • the ORF encodes a protein consisting of 425 amino acid residues and there existed ten putative transmembrane domains.
  • Figure 26 depicts the hydrophobicity/hydrophilicity profile, obtained by the Kyte-Doolittle method, of the present protein. In vitro translation resulted in formation of a translation product of high molecular weight.
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. Z43270) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. N34717) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • ⁇ HP10644> (SEQ ID NOS: 68, 78, and 88) Determination of the whole base sequence of the cDNA insert of clone HP10644 obtained from cDNA library of the human retinoblastoma cell line WERI-RB revealed the structure consisting of a 221-bp 5 '-untranslated region, a 1191-bp ORF, and a 204-bp 3 ' -untranslated region.
  • the ORF encodes a protein consisting of 396 amino acid residues and there existed two putative transmembrane domains.
  • Figure 28 depicts the hydrophobicity/hydrophilicity profile, obtained by the Kyte-Doolittle method, of the present protein.
  • the search of the protein data base using the amino acid sequence of the present protein revealed that the protein was similar to the Caenorhabiditis elegans hypothetical protein B0511.8 (GenBank Accession No. AF067608).
  • Table 20 shows the comparison between amino acid sequences of the human protein of the present invention (HS) and the Caenorhabiditis elegans hypothetical protein B0511.8 (CE) .
  • the marks of -, *, and . represent a gap, an amino acid residue identical with that of the protein of the present invention, and an amino acid residue similar to that of the protein of the present invention, respectively.
  • the both proteins shared a homology of 31.3% in the region of 361 amino acid residues other than the N-terminal region and the C-terminal region.
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. AA917816) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. N48700) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • ⁇ HP03194> (SEQ ID NOS: 91, 101, and 111) Determination of the whole base sequence of the cDNA insert of clone HP03194 obtained from cDNA library of human epidermoid carcinoma cell line KB revealed the structure consisting of a 120-bp 5 ' -untranslated region, a 912-bp ORF, and a 2406-bp 3 '-untranslated region.
  • the ORF encodes a protein consisting of 303 amino acid residues and there existed four putative transmembrane domains.
  • Figure 31 depicts the hydrophobicity/hydrophilicity profile, obtained by the Kyte-Doolittle method, of the present protein. In vitro translation resulted in formation of a translation product of high molecular weight.
  • the search of the protein data base using the amino acid sequence of the present protein revealed that the protein was similar to the mouse hyperpolarization-activated cation channel HAC3 (GenBank Accession No. AJ225124) .
  • Table 21 shows the comparison between amino acid sequences of the human protein of the present invention (HS) and the mouse hyperpolarization-activated cation channel HAC3 (MM) .
  • the marks of -, *, and . represent a gap, an amino acid residue identical with that of the protein of the present invention, and an amino acid residue similar to that of the protein of the present invention, respectively.
  • the both proteins shared a homology of 92.5% in the N-terminal region of 293 amino acid residues.
  • ⁇ HP03219> (SEQ ID NOS: 92, 102, and 112) Determination of the whole base sequence of the cDNA insert of clone HP03219 obtained from cDNA library of human lymphoma cell line U937 revealed the structure consisting of a 55-bp 5 '-untranslated region, a 852-bp ORF, and a 237-bp 3 '-untranslated region.
  • the ORF encodes a protein consisting of 283 amino acid residues and there existed four putative transmembrane domains.
  • Figure 32 depicts the hydrophobicity/hydrophilicity profile, obtained by the Kyte- Doolittle method, of the present protein. In vitro translation resulted in formation of a translation product of high molecular weight.
  • Table 22 shows the comparison between amino acid sequences of the human protein of the present invention (HS) and the human putative membrane protein 54TMp (TM).
  • HS human protein of the present invention
  • TM human putative membrane protein 54TMp
  • the marks of -, *, and . represent a gap, an amino acid residue identical with that of the protein of the present invention, and an amino acid residue similar to that of the protein of the present invention, respectively.
  • the both proteins shared a homology of 56.5% in the entire region.
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. H86659) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. AA744858) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • ⁇ HP03237> (SEQ ID NOS: 94, 104, and 114) Determination of the whole base sequence of the cDNA insert of clone HP03237 obtained from cDNA library of human fibrosarcoma cell line HT-1080 revealed the structure consisting of a 101-bp 5 '-untranslated region, a 549-bp ORF, and a 1106-bp 3 ' -untranslated region.
  • the ORF encodes a protein consisting of 182 amino acid residues and there existed four putative transmembrane domains.
  • Figure 34 depicts the hydrophobicity/hydrophilicity profile, obtained by the Kyte-Doolittle method, of the present protein.
  • Table 24 shows the comparison between amino acid sequences of the human protein of the present invention (HS) and the human intestinal membrane A4 protein (IM).
  • HS human protein of the present invention
  • IM human intestinal membrane A4 protein
  • the marks of -, *, and . represent a gap, an amino acid residue identical with that of the protein of the present invention, and an amino acid residue similar to that of the protein of the present invention, respectively.
  • the both proteins shared a homology of 32.4% in the intermediate region of 111 amino acid residues.
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. R14227) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. R09702) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • Table 26 shows the comparison between amino acid sequences of the human protein of the present invention (HS) and the Schizosaccharomyces pombe hypothetical protein (SP) .
  • the marks of -, *, and . represent a gap, an amino acid residue identical with that of the protein of the present invention, and an amino acid residue similar to that of the protein of the present invention, respectively.
  • the both proteins shared a homology of 43.4% in the entire region.
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. T30721) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. AA043039) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. W26443) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. T85006) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. AA336522) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. AA054017) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • ⁇ HP03266> (SEQ ID NOS: 122, 132, and 142) Determination of the whole base sequence of the cDNA insert of clone HP03266 obtained from cDNA library of human fibrosarcoma cell line HT-1080 revealed the structure consisting of a 69-bp 5 ' -untranslated region, a 957-bp ORF, and a 1464-bp 3 '-untranslated region.
  • the ORF encodes a protein consisting of 318 amino acid residues and there existed one putative transmembrane domain at the N-terminus.
  • Figure 42 depicts the hydrophobicity/hydrophilicity profile, obtained by the Kyte-Doolittle method, of the present protein. In vitro translation resulted in formation of a translation product of 34 kDa that was almost identical with the molecular weight of 35,363 predicted from the ORF.
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. D17020) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • Table 30 shows the comparison between amino acid sequences of the human protein of the present invention (HP) and the Schizosaccharomyces pombe hypothetical protein 9.0kDa (SP).
  • HP human protein of the present invention
  • SP Schizosaccharomyces pombe hypothetical protein 9.0kDa
  • the marks of -, *, and . represent a gap, an amino acid residue identical with that of the protein of the present invention, and an amino acid residue similar to that of the protein of the present invention, respectively.
  • the both proteins shared a homology of 45.7% in the entire region. Table 30
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. AA853098) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • ⁇ HP10665> (SEQ ID NOS: 124, 134, and 144) Determination of the whole base sequence of the cDNA insert of clone HP10665 obtained from cDNA library of human fibrosarcoma cell line HT-1080 revealed the structure consisting of a 31-bp 5' -untranslated region, a 744-bp ORF, and a 142-bp 3'-untranslated region.
  • the ORF encodes a protein consisting of 247 amino acid residues and there existed a putative secretory signal at the N-terminus.
  • Figure 44 depicts the hydrophobicity/hydrophilicity profile, obtained by the Kyte-Doolittle method, of the present protein.
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. AF086533) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • the search of the protein data base using the amino acid sequence of the present protein revealed that the protein was similar to the Caenorhabditis elegans hypothetical protein CELM03F8.2 (GenBank Protein ID No. AAB65910).
  • Table 31 shows the comparison between amino acid sequences of the human protein of the present invention (HP) and the Caenorhabditis elegans hypothetical protein CELM03F8.2 (CE) .
  • the marks of -, *, and . represent a gap, an amino acid residue identical with that of the protein of the present invention, and an amino acid residue similar to that of the protein of the present invention, respectively.
  • the both proteins shared a homology of 39.6% in the N-terminal region of 376 residues.
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. Z46196) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. AA357141) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. R96413) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • the search of the GenBank using the base sequences of the present cDNA has revealed the registration of sequences that shared a homology of 90% or more (for example, Accession No. AA356139) among ESTs. However, since they are partial sequences, it can not be judged whether or not they encode the same protein as the protein of the present invention.
  • ⁇ HP10683> (SEQ ID NOS: 130, 140, and 150) Determination of the whole base sequence of the cDNA insert of clone HP10683 obtained from cDNA library of the human lymphoma cell line U937 revealed the structure consisting of a 25-bp 5 ' -untranslated region, a 525-bp ORF, and a 714-bp 3 ' -untranslated region.
  • the ORF encodes a protein consisting of 174 amino acid residues and there existed one putative transmembrane domain.
  • Figure 50 depicts the hydrophobicity/hydrophilicity profile, obtained by the Kyte-Doolittle method, of the present protein.
  • the present invention provides human proteins having hydrophobic domains, DNAs encoding these proteins, and expression vectors for these DNAs as well as eukaryotic cells expressing these DNAs. Since all of the proteins of the present invention are secreted or exist in the cell membrane, they are considered to be proteins controlling the proliferation and/or the differentiation of the cells. Accordingly, the proteins of the present invention can be employed as pharmaceuticals such as carcinostatic agents which act to control the proliferation and/or the differentiation of the cells, or as antigens for preparing antibodies against these proteins.
  • the DNAs of the present invention can be utilized as probes for the genetic diagnosis and gene sources for the gene therapy. Furthermore, the DNAs can be utilized for large-scale expression of these proteins. Cells into which these genes are introduced to express these proteins, can be utilized for detection of the corresponding receptors or ligands, screening of novel small molecule pharmaceuticals and the like.
  • the present invention also provides genes corresponding to the polynucleotide sequences disclosed herein.
  • “Corresponding genes” are the regions of the genome that are transcribed to produce the mRNAs from which cDNA polynucleotide sequences are derived and may include contiguous regions of the genome necessary for the regulated expression of such genes. Corresponding genes may therefore include but are not limited to coding sequences, 5 ' and 3 ' untranslated regions, alternatively spliced exons, introns, promoters, enhancers, and silencer or suppressor elements. The corresponding genes can be isolated in accordance with known methods using the sequence information disclosed herein.
  • Such methods include the preparation of probes or primers from the disclosed sequence information for identification and/or amplification of genes in appropriate genomic libraries or other sources of genomic materials.
  • An "isolated gene” is a gene that has been separated from the adjacent coding sequences, if any, present in the genome of the organism from which the gene was isolated. Organisms that have enhanced, reduced, or modified expression of the gene(s) corresponding to the polynucleotide sequences disclosed herein are provided. The desired change in gene expression can be achieved through the use of antisense polynucleotides or ribozymes that bind and/or cleave the mRNA transcribed from the gene (Albert and Morris, 1994, Trends Pharmacol. Sci.
  • Transgenic animals that have multiple copies of the gene(s) corresponding to the polynucleotide sequences disclosed herein, preferably produced by transformation of cells with genetic constructs that are stably maintained within the transformed cells and their progeny, are provided.
  • organisms are provided in which the gene(s) corresponding to the polynucleotide sequences disclosed herein have been partially or completely inactivated, through insertion of extraneous sequences into the corresponding gene(s) or through deletion of all or part of the corresponding gene(s). Partial or complete gene inactivation can be accomplished through insertion, preferably followed by imprecise excision, of transposable elements (Plasterk, 1992, Bioessays 14(9): 629-633; Zwaal et al., 1993, Proc. Natl. Acad. Sci. USA 90(16): 7431-7435; Clark et al., 1994, Proc. Natl. Acad. Sci.
  • Such organisms are useful for the development of non-human models for the study of disorders involving the corresponding gene( s) , and for the development of assay systems for the identification of molecules that interact with the protein produc (s) of the corresponding gene(s).
  • the protein of the present invention is membrane-bound (e.g., is a receptor)
  • the present invention also provides for soluble forms of such protein. In such forms part or all of the intracellular and transmembrane domains of the protein are deleted such that the protein is fully secreted from the cell in which it is expressed.
  • the intracellular and transmembrane domains of proteins of the invention can be identified in accordance with known techniques for determination of such domains from sequence information.
  • Proteins and protein fragments of the present invention include proteins with amino acid sequence lengths that are at least 25% (more preferably at least 50%, and most preferably at least 75%) of the length of a disclosed protein and have at least 60% sequence identity (more preferably, at least 75% identity; most preferably at least 90% or 95% identity) with that disclosed protein, where sequence identity is determined by comparing the amino acid sequences of the proteins when aligned so as to maximize overlap and identity while minimizing sequence gaps.
  • proteins and protein fragments that contain a segment preferably comprising 8 or more (more preferably 20 or more, most preferably 30 or more) contiguous amino acids that shares at least 75% sequence identity (more preferably, at least 85% identity; most preferably at least 95% identity) with any such segment of any of the disclosed proteins.
  • Species homologs of the disclosed polynucleotides and proteins are also provided by the present invention.
  • a "species homologue" is a protein or polynucleotide with a different species of origin from that of a given protein or polynucleotide, but with significant sequence similarity to the given protein or polynucleotide, as determined by those of skill in the art.
  • Species homologs may be isolated and identified by making suitable probes or primers from the sequences provided herein and screening a suitable nucleic acid source from the desired species.
  • the invention also encompasses allelic variants of the disclosed polynucleotides or proteins; that is, naturally- occurring alternative forms of the isolated polynucleotide which also encode proteins which are identical, homologous, or related to that encoded by the polynucleotides.
  • the invention also includes polynucleotides with sequences complementary to those of the polynucleotides disclosed herein.
  • the present invention also includes polynucleotides capable of hybridizing under reduced stringency conditions, more preferably stringent conditions, and most preferably highly stringent conditions, to polynucleotides described herein.
  • stringency conditions are shown in the Table 32 below: highly stringent conditions are those that are at least as stringent as, for example, conditions A-F; stringent conditions are at least as stringent as, for example, conditions G-L; and reduced stringency conditions are at least as stringent as, for example, conditions M-R.
  • the hybrid length is that anticipated for the hybridized region(s) of the hybridizing polynucleotides.
  • the hybrid length is assumed to be that of the hybridizing polynucleotide.
  • the hybrid length can be determined by aligning the sequences of the polynucleotides and identifying the region or regions of optimal sequence complementarity.
  • SSPE 0.15M NaCl, lOmM NaH 2 PO 4 , and 1.25mM EDTA, pH7.4
  • SSC 0.15M NaCl and 15mM sodium citrate
  • T m melting temperature
  • each such hybridizing polynucleotide has a length that is at least 25% (more preferably at least 50%, and most preferably at least 75%) of the length of the polynucleotide of the present invention to which it hybridizes, and has at least 60% sequence identity (more preferably, at least 75% identity; most preferably at least 90% or 95% identity) with the polynucleotide of the present invention to which it hybridizes, where sequence identity is determined by comparing the sequences of the hybridizing polynucleotides when aligned so as to maximize overlap and identity while minimizing sequence gaps.

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Abstract

L'invention concerne des protéines humaines à domaines hydrophobes, des ADN codant pour ces protéines et des vecteurs d'expression pour ces ADN, ainsi que des cellules eucaryotiques exprimant ces ADN.
PCT/JP1999/006412 1998-11-17 1999-11-17 Proteines humaines a domaines hydrophobes et adn codant pour ces proteines WO2000029448A2 (fr)

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AU11819/00A AU1181900A (en) 1998-11-17 1999-11-17 Human proteins having hydrophobic domains and dnas encoding these proteins
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WO2001005972A1 (fr) * 1999-07-20 2001-01-25 Genentech, Inc. Compositions et methodes pour traiter des maladies d'ordre immunologique
WO2001042499A1 (fr) * 1999-12-09 2001-06-14 Sankyo Company, Limited Procede d'essai d'agent curatif ou preventif de l'hyperlipemie
WO2001098503A2 (fr) * 2000-06-21 2001-12-27 Bayer Aktiengesellschaft Regulation d'une enzyme de type serine protease 1 d'eosinophile humain
WO2002085942A2 (fr) * 2001-04-24 2002-10-31 Mcgill University Recepteur accessoire de 150 kda pour le tgf-$g(b).
EP1169433A4 (fr) * 1999-04-15 2003-01-02 Icagen Inc Hac3 humains
EP1268506A1 (fr) * 1999-07-30 2003-01-02 Millennium Pharmaceuticals, Inc. Proteine secretees et leurs applications
FR2849055A1 (fr) * 2002-12-18 2004-06-25 Exonhit Therapeutics Sa Nouvelle cible moleculaire de l'angiogenese et utilisations
US6902892B1 (en) 1998-10-19 2005-06-07 Diadexus, Inc. Method of diagnosing, monitoring, staging, imaging and treating prostate cancer
EP1159413A4 (fr) * 1999-02-26 2005-12-14 Millennium Pharm Inc Proteines secretees et utilisations
EP1642907A2 (fr) * 1999-03-08 2006-04-05 Genentech, Inc. Composition et procédés de diagnostic de tumeurs
EP1842917A1 (fr) * 1998-02-17 2007-10-10 Forschungszentrum Jülich Gmbh Séquences d'un canal d'ions Ih et leur utilisation
JP2008271899A (ja) * 2007-05-01 2008-11-13 Japan Science & Technology Agency 生理活性蛋白質の分泌を促進する新規な遺伝子ファミリー
AU2003291625B2 (en) * 2002-09-16 2009-10-08 Genentech, Inc. Compositions and methods for the treatment of immune related diseases
US7700316B2 (en) * 2001-03-07 2010-04-20 Andre Schuh CD109 nucleic acid molecules, polypeptides and methods of use
US7741029B2 (en) * 2001-03-07 2010-06-22 Andre Schuh Diagnosis and treatment of blood disorders
US7947436B2 (en) 2004-12-13 2011-05-24 Alethia Biotherapeutics Inc. Polynucleotides and polypeptide sequences involved in the process of bone remodeling

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EP1842917A1 (fr) * 1998-02-17 2007-10-10 Forschungszentrum Jülich Gmbh Séquences d'un canal d'ions Ih et leur utilisation
US6902892B1 (en) 1998-10-19 2005-06-07 Diadexus, Inc. Method of diagnosing, monitoring, staging, imaging and treating prostate cancer
US7432064B2 (en) 1998-10-19 2008-10-07 Diadexus, Inc. Method of diagnosing, monitoring, staging, imaging and treating prostate cancer
EP1159413A4 (fr) * 1999-02-26 2005-12-14 Millennium Pharm Inc Proteines secretees et utilisations
EP1642907A2 (fr) * 1999-03-08 2006-04-05 Genentech, Inc. Composition et procédés de diagnostic de tumeurs
EP1642907A3 (fr) * 1999-03-08 2006-06-21 Genentech, Inc. Composition et procédés de diagnostic de tumeurs
EP1169433A4 (fr) * 1999-04-15 2003-01-02 Icagen Inc Hac3 humains
US7169893B2 (en) 1999-04-15 2007-01-30 Icagen, Incorporated Human HAC3
US7153668B2 (en) 1999-04-15 2006-12-26 Icagen, Incorporated Human HAC3
WO2000065067A3 (fr) * 1999-04-23 2001-08-02 Univ Washington Polynucleotides, polypeptides specifiques a la prostate, et leurs procedes d'utilisation
WO2000065067A2 (fr) * 1999-04-23 2000-11-02 University Of Washington Polynucleotides, polypeptides specifiques a la prostate, et leurs procedes d'utilisation
WO2001005972A1 (fr) * 1999-07-20 2001-01-25 Genentech, Inc. Compositions et methodes pour traiter des maladies d'ordre immunologique
EP1268506A4 (fr) * 1999-07-30 2004-07-28 Millennium Pharm Inc Proteine secretees et leurs applications
EP1268506A1 (fr) * 1999-07-30 2003-01-02 Millennium Pharmaceuticals, Inc. Proteine secretees et leurs applications
WO2001042499A1 (fr) * 1999-12-09 2001-06-14 Sankyo Company, Limited Procede d'essai d'agent curatif ou preventif de l'hyperlipemie
WO2001098503A2 (fr) * 2000-06-21 2001-12-27 Bayer Aktiengesellschaft Regulation d'une enzyme de type serine protease 1 d'eosinophile humain
US7060810B2 (en) 2000-06-21 2006-06-13 Bayer Aktiengesellschaft Regulation of human eosinophil serine protease 1-like enzyme
WO2001098503A3 (fr) * 2000-06-21 2002-11-07 Bayer Ag Regulation d'une enzyme de type serine protease 1 d'eosinophile humain
US7741029B2 (en) * 2001-03-07 2010-06-22 Andre Schuh Diagnosis and treatment of blood disorders
US7700316B2 (en) * 2001-03-07 2010-04-20 Andre Schuh CD109 nucleic acid molecules, polypeptides and methods of use
US8318909B2 (en) 2001-03-07 2012-11-27 Andre Schuh Antibodies for diagnosis and treatment of blood platelet alloimmune disorders
US7173002B2 (en) * 2001-04-24 2007-02-06 Mcgill University 150 KDA TGF-B1 accessory receptor acts a negative modulator of TGF-B signaling
WO2002085942A3 (fr) * 2001-04-24 2003-10-09 Univ Mcgill Recepteur accessoire de 150 kda pour le tgf-$g(b).
WO2002085942A2 (fr) * 2001-04-24 2002-10-31 Mcgill University Recepteur accessoire de 150 kda pour le tgf-$g(b).
AU2003291625B2 (en) * 2002-09-16 2009-10-08 Genentech, Inc. Compositions and methods for the treatment of immune related diseases
FR2849055A1 (fr) * 2002-12-18 2004-06-25 Exonhit Therapeutics Sa Nouvelle cible moleculaire de l'angiogenese et utilisations
US7947436B2 (en) 2004-12-13 2011-05-24 Alethia Biotherapeutics Inc. Polynucleotides and polypeptide sequences involved in the process of bone remodeling
US8444975B2 (en) 2004-12-13 2013-05-21 Alethia Biotherapeutics Inc. Method for inhibiting bone resorption
JP2008271899A (ja) * 2007-05-01 2008-11-13 Japan Science & Technology Agency 生理活性蛋白質の分泌を促進する新規な遺伝子ファミリー

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